During fasting, the natural metabolite glycerol (propane-1,2,3-triol), a component of triacylglycerols, is liberated in the process of lipolysis. Through the final steps of the gluconeogenetic pathway it is easily converted to glucose, mainly in the liver. It has been shown that the regulation of hepatic glycerol metabolism plays a pivotal role in fasting [Patsouris, D. et al., J. Clin. Invest. 114: 4-103 (2004)].
Assuming a total energy expenditure of 10.000 kJ per day, about 250 g of body fat will have to be oxidized to meet the energy demand. This is equivalent to about 1 mol of typical free fatty acids such as palmitic acid or stearic acid. In the context of lipolysis, this means a liberation of, at best, ⅓ mol of glycerol, i.e. about 30 g, which may be converted to 30 g glucose. The daily glucose demand of the adult human brain and of other strictly glucose-dependent tissues is in the order of 100 g-160 g. As a consequence of this physiological glycerol deficit in fasting humans, other glucose precursors, in particular amino acids, become substrates of gluconeogenesis, resulting in undesirable protein losses, in particular during the early stages of fasting [Owen, O. E. et al., Am. J. Clin. Nutr. 68:12-34 (1998)]. Animals, with smaller brain mass in relation to their body weight than humans, generally show a more favourable balance of glucose demand and glycerol liberation during fasting. Some species thus manage to survive long periods of starvation without protein losses [Bernard, S. F. et al., J. Exp. Biol. 205:2745-2754 (2002)]. It has been shown in mammals that infusion of glycerol inhibits gluconeogenesis from other precursors [Steele, R. et al., Am. J. Physiol. 221:883-888 (1971)]. This generally suggests that gluconeogenetic protein losses in fasting humans may be reduced by glycerol supplementation. In contrast to ingestion of glucose and other carbohydrates, glycerol supplementation does not increase plasma glucose concentrations in healthy fasting subjects. Moreover, glycerol application does not increase hepatic glucose production beyond fasting control conditions without exogenous glycerol load [Trimmer, J. K. et al., Am. J. Physiol. 280:E657-E668 (2001)]. This means that glycerol supplementation will not affect the metabolic state of fasting: fatty acid oxidation remains the major source of energy supply. Since adequate glycerol supplementation during fasting improves glucose availability, it reduces undesirable effects such as hypoglycaemia, gluconeogenetic protein losses and increased levels of ketone bodies.
In addition to endogenous glucose production, hydration is a critical topic during fasting. Reducing food intake also reduces water intake. Fasting subjects practically never adapt their drinking habits spontaneously and sufficiently to compensate for these losses. Nutritional consultants therefore prescribe strict schemes of fluid intake for fasting subjects. Simply drinking increased amounts of pure water rarely meets with success, because it decreases the osmolarity of body fluids, which in turn leads to rapid water excretion via the Adiuretin pathway. Application of iso- or hyperosmotic glycerol solutions during short- and long-term fasting will not only provide a substrate for gluconeogenesis but also induce a longer-lasting hydration. As stated supra, glycerol is a natural metabolite and non-toxic in large doses—European food laws permit application quantum satis. When consumed, it is rapidly absorbed from the gastrointestinal tract. Distribution space of glycerol depends on plasma concentrations: In the range of low plasma concentrations (<5 mmol/l) it approximates 0.3 l per kg body weight. With larger concentrations, distribution space increases to about 0.6 I/kg, i.e. near to total body water volume [Beylot, M. et al., J. Lipid. Res. 28:414-422 (1987); Robergs, R. A. et al., Sports Med. 26:145-167 (1998)]. Below plasma concentrations of 1 mmol/l, glycerol is fully reabsorbed by the kidneys. Above this limit, both tubular reabsorption and renal excretion increase over a large range of concentrations.
Besides serving as substrate for gluconeogenesis, glycerol can be oxidized in many tissues or be used for re-esterification of fatty acids [van Hall, G. et al., J. Physiol. 543:1047-1058 (2002)]. This, however, occurs only at a slow rate, so that the disappearance rate of glycerol is much slower than that of, for example, glucose. Given the slow disappearance rate and the large distribution volume, isoosmotic or hyperosmotic glycerol solutions will lead to long-lasting hydration effects.
Persons facing situations where urination is impossible or inconvenient (e.g. long distance car driving, various occupational contexts), tend to abstain from fluid consumption in order to reduce the need to urinate. Elderly people, who per se display reduced fluid intake, frequently undergo deliberate dehydration in the late afternoon and evening hours in order to avoid frequent urination overnight. The situation gets worse if neither fluid nor food is consumed, because hypoglycaemia may add to dehydration. Both hypoglycaemia and dehydration reduce mental and physical fitness, which may be hazardous in some situations. In the elderly, for example, it will increase the risk of falling. In this field of application, subjects may also benefit from the hydrating and anti-hypoglycaemic effect of the present glycerol solutions.
WO 94/25031 discloses an exercise regimen which enhances exercise endurance and performance. The regimen includes pre-exercise hydration with a glycerol solution combined with hydration during exercise with a glycerol-based solution to prolong hydration effects. The first pre-exercise glycerol solution regimen begins 2 h prior to exercise and ends ½ h before exercise begins. The hydration during exercise regimen combines glycerol with carbohydrate and sodium to additionally compensate for glycogen depletion and the sweat losses of sodium during exercise. Further WO 06/008552 and CA-A-2233033 disclose aqueous (re)hydrating compositions comprising glycerol.
The problem underlying present invention is the insufficient endogenous glycerol supply and the dehydration seen in deliberately fasting subjects as well as in subjects trying to avoid urination. The present invention presents glycerol as suitable agent that helps preventing hypoglycaemia, dehydration and gluconeogenetic protein losses in such contexts.